To contain, or not to contain: that is (no longer) the question...
Until recently, containment in pharmaceutical solid dosage was approached with a ON/OFF logic: if the product is dangerous for the operator, then containment measures must be implemented, if not, standard equipment can be used. In recent years contained solid dosage manufacturing has been undergoing several changes. Firstly, requests for equipment fitted with technical solutions to limit contact between the operator and the product have intensified as a result of a double trend: on one hand the increase in High Potency Active Pharmaceutical Ingredients (HPAPI), and on the other side growing attention with regard to operator safety.
But even more important, the approach to containment has been evolving to incorporate a risk-based logic. In the EU-GMP guidelines issued on 1st March 2015, the question has changed from a YES/NO type (“is the product dangerous for the operator?”) to a more complex and qualitative set of questions: “how dangerous is the product for the operator?” and “why?” and “when, in which process phase?”.
Both for equipment users and manufacturers, this change in perspective has led to the search and the development of a wide range of technical solutions, granting different degrees of containment, and to a common analytic approach to decide which measure should be applied to each specific product and manufacturing process.
2. Evolution of containment
Containment is certainly not a new issue. As with many modern technologies such as mobile phones and the internet, it originates in a military context more or less 75 years ago, and in the 1960’s it becomes a topic that starts to seriously interest the pharmaceutical industry with the growing incidence of cytostatic drugs. Today, HPAPI include both small molecules and biological substances: oncology is the key driver behind the growth of this segment, with around 60% of the new HPAPI being developed for the treatment of cancer.
Roots Analysis estimates that over 25% of the total drugs world-wide can be classified as highly potent: substances may include antibody drug conjugates but also hormones or narcotics, and besides cancer they address a number of growing chronic diseases like CNS, musculoskeletal and metabolic disorders. According to Grand View Research, the global HPAPI’s market is expected to reach USD 34.8 billion by 2025, with a double digit growth rate and an increasing incidence of generic HPAPI’s.
Containment measures for the manufacturing of HPAPI are intended to prevent exposure of operators and environment to hazardous substances, and in multi-purpose facilities to avoid cross contamination between different products. Containment strategies can be based on a combination of Personnel Protective Equipment (PPE) and Standard Operating Procedures (SOPs): while this approach needs a lower initial investment, it heavily relies on the personal behaviour of operators, requires constant training to be effective and can generate a higher Total Cost of Ownership in the long term. As an alternative, completely automatic technical solutions can be fitted on the equipment: while usually this implies a higher investment, automation ensures repeatability and effectiveness in the long term.
Launched by IMA in 1995, Comprima already in the standard configuration implements a series of technological features and devices that allow for the easy application of high containment technical solutions, making it suitable to process OEB 5 substances. Process area completely isolated from mechanical area, negative pressure in the processing area, powder wetting to dump airborne substances combined with automatic Clean-In-Place systems are some of the most notable innovations introduced already 20 years ago. The same solutions and know-how have been applied over the years in other machines built by IMA for solid dose manufacturing, and with excellent results.
3. The need for a modulated response
However, the pharmaceutical industry is evolving fast and high containment technologies in a number of instances can be overkill. The general trend in increased potency of API does not mean that only OEB 5 products are growing, but also a general increase in OEB 4 and 3 substances. Additionally, the overall concern for operator safety and environmental protection makes for a certain level of containment to be implemented also for OEB 3 products that in the past were probably run on standard equipment.
Whereas 20 years ago, one of the key growth drivers in the industry was the development of HPAPI’s, requiring the strictest containment measures, today the industry needs a more articulated response from equipment manufacturers. This is why over 20 years since Comprima hit the market, IMA has a broad range of containment solutions that stem from an in-depth risk analysis, almost identical to the analysis carried out by pharmaceutical companies handling more or less toxic API’s.
OEB 5 – Highly toxic
< 1 μg/m³
OEB 4 – Toxic
OEB 3 – Less toxic
OEB 2 – Almost nontoxic
OEB 1 – Nontoxic
Table 1: OEB and OEL product classification
OEB (Occupational Exposure Band): toxicity level of the product based on health outcomes and potency considerations.
OEL (Occupational Exposure Limit): safe concentration of hazardous airborne substances considering 8-hour workday exposure; not detrimental to health even if exposure occurs repeatedly day after day.
4. FMECA Risk Analysis background for calibrated containment solutions
The development of technical solutions for this new approach to containment must necessarily start from embracing the same approach to the topic used by the pharmaceutical companies, and adopt the very same risk analysis principles used in the industry to ascertain the hazards for each and every product, from OEB 1 to OEB 5 degree toxicity.
Once the risk analysis has taken into consideration the widest possible range of scenarios, the equipment manufacturer is in a position to develop new technological solutions to effectively satisfy the full range of containment needs, from low through moderate to high. Taking into consideration the entire process from loading to unloading, in particular for the tableting and capsule-filling manufacturing phases, IMA ran a comprehensive FMECA Analysis (Failure Mode, Effects and Criticality Analysis) to establish a complete picture of potential risks in countless environments, process types and software failure situations. This represents the standard method recommended by ICH Q9 (International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals For Human Use – “Quality Risk Management: Q9” – Nov. 2005) as well as being in line with GAMP 5 – A Risk Based Approach to Compliant GxP Computerized System. Each single function and sub-function in the process was assessed for risks, carefully identifying potential failures and potential effects. Once identified, each potential failure was evaluated according to the following criteria: severity, occurrence and detectability.
At each of these three criteria, a value of high, medium or low has been assigned. Direct correlation between risk severity values and risk occurrence values enables to obtain the Risk Class of each potential failure, which can be high, medium and low. Once the risk class has been established, the third criteria, detectability, is introduced and is placed in relation to risk class to produce what is called risk priority. This too can be classified as high, medium or low. Consequently according to the risk priority for each potential failure, we are able to establish the corresponding corrective action needed to reduce the risk to an acceptable degree. For example intermediate containment solutions can be implemented.
This analysis is the key to understanding exactly what is required to reduce risks accordingly. This analysis has led IMA to create a range of dedicated containment solutions ensuring efficiency and security whatever the level of toxicity.
5. Targeted containment strategies
The containment strategy has been based on the risk analysis referring to the entire process. This includes product transfer at machine inlet and outlet, tableting and filling stages, as well as end-of-batch management and cleaning procedures, undoubtedly a critical phase.
IMA has considered the following areas:
• machine configuration
• powder loading and loading of empty capsules
(for capsule filling machines)
• capsule polishing/de-dusting and metal checking
• unloading of tablets/filled capsules
• aspiration and filtration of dust
• IPC and weight check
• end of process and cleaning.
Based on the gathered data and on all aspects of the process, IMA has developed a 3-tier offering which responds in a contextual fashion to four process circumstances (see Table 2) . Broadly speaking, the first category called Dust Tight ensures effective containment up to and including OEB 3 level toxic API’s during normal production conditions. Dry Containment solutions are suitable for OEB 4 level and THC (Total High Containment) category equipment will handle OEB 5 toxic products throughout the process.
A closer look at the approach elaborated by IMA shows how a wider range of equipment covers all requirements without the need to overkill. All solutions supplied by IMA will be fitted with devices ensuring appropriate degrees of safety according to product and process characteristics and criticalities as identified by the Risk Analysis, and according to specific customer demands. Process area enclosed by dust-tight gaskets and V-Ring seals or inflatable seals, negative pressure differential, interlock system for machine doors and password protection to unlock doors, Venturi system for negative pressure in case of blackout or aspiration failure: these are some of the technical solutions that can be applied to determine a specific containment level. But also aspiration lances, glove ports and RTP’s, dust-tight systems or high containment valves applied to loading of product and empty capsule, and many other specific systems can be applied for an installation tailored to the individual need.
Facing such a wide range of devices and technical solutions, the Risk Analysis represents the “know why”, the rational to understand how they should be applied to achieve a containment level which is at the same time effective from both a performance-oriented and economic point of view and not oversized.
THC – Total High Containment
Normal production conditions
Containment level OEB 3 ensured
Containment level OEB 4 ensured
Containment level OEB5 ensured
Emergency intervention during production
Relies on customer SOP and PPE if necessary
Relies on customer SOP and PPE, but some technical solutions are implemented to allow a certain level of intervention without breaking the containment
Glove ports, Rapid Transfer Ports and other measures to ensure OEB 5
End of batch management
Relies on customer SOP and PPE if necessary
Relies on customer SOP and PPE, but technical solutions are implemented to reduce emissions
Containment level OEB 5 ensured
Maintenance and cleaning
Manual cleaning, relies on customer SOP and PPE if necessary
Manual cleaning, relies on customer SOP and PPE if necessary
Airborne dumping and semi-automatic WIP to ensure OEB 5
Table 2: OEB and OEL product classification
Today’s scenario is no longer that of the early 2000’s. Pharmaceutical companies are asking for more than an on/off answer to containment. Increasing product variety, higher API concentrations, greater awareness and concern for safety in the industry are all factors that have led to a need for a well-defined multiple response to containment issues. This is what IMA has achieved through a risk analysis which mirrors the approach pharmaceutical companies adopt. Considering today’s approach to Risk Analysis in the Pharmaceutical Industry covers all aspects of production starting with active ingredient procurement all the way through each production phase, IMA as a key partner to this industry has chosen to adopt the very same approach as this is the best and only way to target the real instances in which containment is required adapting its solutions to the actual needs. Bilaterally endorsed solutions are the most effective answer today. So let’s forget any Shakespearean doubts about containment and look toward a new future.